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Preparation method and application of a novel pt(iv) complex with tumor targeting

A tumor-targeting and complex technology, applied in platinum-based organic compounds, platinum-group organic compounds, anti-tumor drugs, etc., can solve the problems of difficult combined chemotherapy regimens, low activity, and different mechanisms of action, so as to avoid drug resistance Drug properties, simple and easy operation, beneficial to the effect of industrial production

Active Publication Date: 2022-03-15
KUNMING GUIYAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it has the advantage of oral activity, its activity is not outstanding compared with cisplatin and carboplatin in terms of curative effect; at the same time, most of the current clinical chemotherapy uses combination drugs, and most of the antineoplastic drugs combined with platinum drugs are administered intravenously. The injection form has the best curative effect, so it is difficult to find a combined chemotherapy regimen for oral administration. A series of problems have led to JM216 entering clinical trials for more than ten years and still not being on the market.
Since the non-leaving group of Satraplatin introduces an asymmetric amine ligand, its mechanism of action is somewhat different from that of classic platinum drugs on the market

Method used

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  • Preparation method and application of a novel pt(iv) complex with tumor targeting
  • Preparation method and application of a novel pt(iv) complex with tumor targeting
  • Preparation method and application of a novel pt(iv) complex with tumor targeting

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Embodiment 1: prepare complex (A-1) as shown in I formula, namely:

[0086]

[0087] Weigh 1 g (1.6 mol) of the Pt(IV) complex precursor containing two hydroxyl groups prepared in step 5, dissolve it in an appropriate amount of DMSO, and place it in a 100 mL round bottom flask. Weigh 0.95 g (1.6 mol) of the biotin succinimide ester prepared in step 9 and add it to the above reaction solution, put it in a water bath at 60°C, and stir evenly overnight. After the reaction was finished, a small amount of undissolved solid in the reaction solution was removed by suction filtration, and the filtrate was collected. The filtrate was recrystallized with diethyl ether and methanol at a volume ratio of 1:1 to precipitate the product, filtered with suction, rinsed with the mother liquor 2 to 3 times, and dried in vacuum to obtain a Pt (IV) Complex 0.4g, its hydrogen spectrum is as follows figure 1 As shown, its mass spectrum is shown as figure 2 shown. Yield: 26.7%. 1 H NM...

Embodiment 2

[0088] Embodiment 2: prepare complex (A-2) as shown in I formula, namely:

[0089]

[0090] Weigh the Pt(IV) complex precursor 1g (1.12mol) containing monochlorine and monohydroxyl prepared in step 7 and dissolve it in an appropriate amount of DMF solvent, then add condensing agent TBTU 1.1g (1.12mol) and triethylamine 0.24 g (1mol), add to the reaction system, and stir evenly in a water bath at 40°C. Weigh 0.526g (0.499mol) of biotin and add it to the reaction solution, and continue the reaction overnight. After the reaction was finished, filter with suction to remove a small amount of undissolved solid in the reaction solution, and collect the filtrate. Add appropriate amount of CH to the reaction solution 2 Cl 2 Extract with purified water for 3 times to remove the condensing agent in the reaction solution, collect the organic phase liquid, evaporate and concentrate to remove the organic solvent, the product is recrystallized with ether and methanol with a volume rati...

Embodiment 3

[0091] Embodiment 3: prepare complex (A-3) as shown in I formula, namely:

[0092]

[0093]Weigh 1 g (1.6 mol) of the Pt(IV) complex precursor containing two hydroxyl groups prepared in step 6, dissolve it in an appropriate amount of DMSO, and place it in a 100 mL round bottom flask. Weigh 0.95 g (1.6 mol) of the biotin succinimide ester prepared in step (9) and add it to the above reaction solution, place in a water bath at 60°C, and stir evenly overnight. After the reaction was finished, a small amount of undissolved solid in the reaction solution was removed by suction filtration, and the filtrate was collected. The filtrate was recrystallized with diethyl ether and methanol at a volume ratio of 1:1 to precipitate the product, filtered with suction, rinsed with the mother liquor 2 to 3 times, and dried in vacuum to obtain a Pt (IV) complex 0.48g, its hydrogen spectrogram is as Figure 5 As shown, its mass spectrum is as Figure 6 shown. Yield: 32.00%. 1 H NMR (600MH...

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Abstract

The invention discloses a novel Pt(IV) complex with tumor targeting, which has the structure of formula I or formula II. The invention discloses a preparation method of a novel Pt(IV) complex with tumor targeting, which retains the asymmetric ammonia ligand of the Saite platinum carrier group, and introduces a biotin ligand with targeting effect at one axial end , the introduction of chloride at the other end reduces the negative value of the oxidation-reduction potential of the platinum complex and increases the reduction kinetics or retains a hydroxyl group at the other end so that the Pt(IV) complex enters the human body and is conducive to the preferential combination with the reducing agent in the body, reducing to Pt(II) complexes to achieve the effect of treating tumors. It has anti-tumor activity against specific tumors and can reduce its toxic and side effects. At the same time, the raw materials used are cheap and easy to obtain, the method is simple and easy, the conditions are mild, the operation is easy, and the method is suitable for large-scale production. Z is Cl ‑ ,

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method and application of a novel Pt(IV) complex with tumor targeting. Background technique [0002] As the second leading cause of death among diseases, cancer not only seriously threatens human life and health, but also creates a heavy burden on families, society and the country, and interferes with my country's economic construction and social development. It is a very prominent social public health problem. question. Since Rosenberg et al. discovered that cisplatin has anticancer activity in 1967, cisplatin, as a high-efficiency antitumor drug for clinical chemotherapy, has been widely used in the treatment of solid tumors, including testicular cancer, ovarian cancer, uterine cancer, lung cancer and Bladder cancer, etc. Although cisplatin exhibits broad-spectrum anti-cancer properties, cisplatin lacks selectivity for tumor cells and has fatal dama...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F15/00A61P35/00
CPCC07F15/0093A61P35/00
Inventor 普绍平高传柱蔡林祥丛艳伟彭娟王应飞刘其星张林涛陈红娟
Owner KUNMING GUIYAN PHARMA
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